tbuckley/cabot-search huggingface dataset:
Impact of testing on Clostridioides difficile infection in hospitals across Europe: a mathematical model
Authors: Emily Agnew, Kerrie A. Davies, Virginie F. Viprey, Stephanie Evans, Georgina L. Davis, Russell Hope, Mark H. Wilcox, Sebastian M. Wingen-Heimann, Julie V. Robotham
Journal: Clinical Microbiology and Infection (2023)

The prevalence of Clostridioides difficile infection (CDI) has been shown to vary markedly between European countries, both in hospitals and in the community. Determining the true prevalence has proven challenging. Without systematic testing in hospitals, the unchecked transmission of CDI can lead to large outbreaks in more susceptible cohorts. We investigate the success of CDI surveillance and control measures across Europe, by examining the dynamics of disease spread from the community into a hospital setting. We focus on national differences, such as variability in testing and sampling, disease prevalence in communities and hospitals, and antimicrobial usage.We developed a stochastic, compartmental, dynamic mathematical model parameterized using sampling and testing rate data from COMBACTE-CDI, a multicountry study in which all diarrhoeal stool samples (N = 3163) from European laboratories were tested for CDI, and data for antimicrobial usage and incidence of hospital cases sourced from the European Centre for Disease Prevention and Control.The framework estimates the prevalence of CDI among hospital patients across European countries and explores how national differences impact the dynamics, transmission, and relative incidence of CDI within the hospital setting. The model illustrates the mechanisms influencing these national differences, namely, antimicrobial usage rates, national sampling and testing rates, and community prevalence of CDI.Differential costs for testing and practicalities of scaling up testing mean every country needs to consider balancing CDI testing costs against the costs of treatment and care of patients with CDI.
Olfactory dysfunction after COVID‐19: metanalysis reveals persistence in one-third of patients 6 months after initial infection
Authors: Siqi Hu, Shenghui Zhang, Yao You, Jiake Tang, Chen Chen, Chunyi Wang, Wen Wen, Mingwei Wang, Juan Chen, Lin Luo, Yongran Cheng, Mengyun Zhou, Xuezhi Zhao, Tao Tan, Guanming Qi, Zhanhui Feng
Journal: Journal of Infection (2023)
ASH2L Controls Ureteric Bud Morphogenesis through the Regulation of RET/GFRA1 Signaling Activity in a Mouse Model
Authors: Ziyi Zhao, Xuantong Dai, Gengru Jiang, Fujun Lin
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Causes of congenital anomalies of the kidney and urinary tract (CAKUT) remain unclear. The authors investigated whether and how inactivation of Ash2l —which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide histone H3 lysine K4 (H3K4) methylation—might contribute to CAKUT. In a mouse model, inactivation of Ash2l in the ureteric bud (UB) lineage led to CAKUT-like phenotypes. Removal of ASH2L led to deficient H3K4 trimethylation, which slowed cell proliferation at the UB tip, delaying budding and impairing branching morphogenesis. The absence of ASH2L also downregulated the expression of Ret , Gfra1 , and Wnt11 genes involved in RET/GFRA1 signaling. These findings identify ASH2L-mediated H3K4 methylation as an upstream epigenetic regulator of signaling crucial for UB morphogenesis and indicate that deficiency or dysregulation of these processes may lead to CAKUT. Background Ureteric bud (UB) induction and branching morphogenesis are fundamental to the establishment of the renal architecture and are key determinants of nephron number. Defective UB morphogenesis could give rise to a spectrum of malformations associated with congenital anomalies of the kidney and urinary tract (CAKUT). Signaling involving glial cell line–derived neurotrophic factor and its receptor rearranged during transfection (RET) and coreceptor GFRA1 seems to be particularly important in UB development. Recent epigenome profiling studies have uncovered dynamic changes of histone H3 lysine K4 (H3K4) methylation during metanephros development, and dysregulated H3K4 methylation has been associated with a syndromic human CAKUT. Methods To investigate whether and how inactivation of Ash2l , which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide H3K4 methylation, might contribute to CAKUT, we inactivated Ash2l specifically from the UB lineage in C57BL/6 mice and examined the effects on genome-wide H3K4 methylation and metanephros development. Genes and epigenome changes potentially involved in these effects were screened using RNA-seq combined with Cleavage Under Targets and Tagmentation sequencing. Results UB-specific inactivation of Ash2l caused CAKUT-like phenotypes mainly involving renal dysplasia at birth, which were associated with deficient H3K4 trimethylation. Ash2l inactivation slowed proliferation of cells at the UB tip, delaying budding and impairing UB branching morphogenesis. These effects were associated with downregulation of Ret , Gfra1 , and Wnt11 , which participate in RET/GFRA1 signaling. Conclusions These experiments identify ASH2L-dependent H3K4 methylation in the UB lineage as an upstream epigenetic regulator of RET/GFRA1 signaling in UB morphogenesis, which, if deficient, may lead to CAKUT.
Re: Melline G.M. Schilham, Mark Rijpkema, Tom Scheenen, et al. How Advanced Imaging Will Guide Therapeutic Strategies for Patients with Newly Diagnosed Prostate Cancer in the Years to Come. Eur Urol 2022;82:578–80
Authors: Francesco Montorsi, Simone Scuderi, Alberto Briganti, Giorgio Gandaglia
Journal: European Urology (2023)
Re: Sigrid V. Carlsson, Rebecka Arnsrud Godtman, Carl-Gustav Pihl, et al. Young Age on Starting Prostate-specific Antigen Testing Is Associated with a Greater Reduction in Prostate Cancer Mortality: 24-Year Follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial. Eur Urol. 2023;83:103–9
Authors: Ki Min Kim, Jae Heon Kim, Benjamin I. Chung
Journal: European Urology (2023)
Clinical and Genetic Characteristics of CKD Patients with High-Risk APOL1 Genotypes
Authors: Mark D. Elliott, Maddalena Marasa, Enrico Cocchi, Natalie Vena, Jun Y. Zhang, Atlas Khan, Sarath Krishna Murthy, Shiraz Bheda, Hila Milo Rasouly, Gundula Povysil, Krzysztof Kiryluk, Ali G. Gharavi
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement APOL1 high-risk genotypes confer a significant risk of kidney disease, but variability in patient outcomes suggests the presence of modifiers of the APOL1 effect. We show that a diverse population of CKD patients with high-risk APOL1 genotypes have an increased lifetime risk of kidney failure and higher eGFR decline rates, with a graded risk among specific high-risk genotypes. CKD patients with high-risk APOL1 genotypes have a lower diagnostic yield for monogenic kidney disease. Exome sequencing revealed enrichment of rare missense variants within the inflammasome pathway modifying the effect of APOL1 risk genotypes, which may explain some clinical heterogeneity. Background APOL1 genotype has significant effects on kidney disease development and progression that vary among specific causes of kidney disease, suggesting the presence of effect modifiers. Methods We assessed the risk of kidney failure and the eGFR decline rate in patients with CKD carrying high-risk ( N =239) and genetically matched low-risk ( N =1187) APOL1 genotypes. Exome sequencing revealed monogenic kidney diseases. Exome-wide association studies and gene-based and gene set–based collapsing analyses evaluated genetic modifiers of the effect of APOL1 genotype on CKD. Results Compared with genetic ancestry-matched patients with CKD with low-risk APOL1 genotypes, those with high-risk APOL1 genotypes had a higher risk of kidney failure (Hazard Ratio [HR]=1.58), a higher decline in eGFR (6.55 versus 3.63 ml/min/1.73 m 2 /yr), and were younger at time of kidney failure (45.1 versus 53.6 years), with the G1/G1 genotype demonstrating the highest risk. The rate for monogenic kidney disorders was lower among patients with CKD with high-risk APOL1 genotypes (2.5%) compared with those with low-risk genotypes (6.7%). Gene set analysis identified an enrichment of rare missense variants in the inflammasome pathway in individuals with high-risk APOL1 genotypes and CKD (odds ratio=1.90). Conclusions In this genetically matched cohort, high-risk APOL1 genotypes were associated with an increased risk of kidney failure and eGFR decline rate, with a graded risk between specific high-risk genotypes and a lower rate of monogenic kidney disease. Rare missense variants in the inflammasome pathway may act as genetic modifiers of APOL1 effect on kidney disease.
Multiomics Analyses Reveal Sex Differences in Mouse Renal Proximal Subsegments
Authors: Lihe Chen, Chung-Lin Chou, Chin-Rang Yang, Mark A. Knepper
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Sex-dependent differences in kidney function are recognized but the underlying molecular mechanisms are largely unexplored. Advances in genomics and proteomic technologies now allow extensive characterization of differences between the same cell types of males and females. Multiomics integrating RNA-seq, ATAC-seq, and proteomics data to investigate differences in gene expression, chromatin accessibility, and protein expression in proximal tubules of male and female mice identified many sex-biased genes and proteins associated with kidney functions, including metabolic and transport processes. Sex differences may also arise from variations of the interaction between transcription factors and accessible chromatin regions. A comprehensive web resource is provided to advance understanding of sex differences in cells of the proximal tubule. Background Sex differences have been increasingly recognized as important in kidney physiology and pathophysiology, but limited resources are available for comprehensive interrogation of sex differences. Methods RNA-seq and ATAC-seq of microdissected mouse proximal tubules and protein mass spectrometry of homogenized perfused mouse kidneys reveal differences in proximal tubule cells of males and females. Results The transcriptomic data indicated that the major differences in the proximal tubules between the sexes were in the S2/S3 segments, and most of the sex-biased transcripts mapped to autosomes rather than to the sex chromosomes. Many of the transcripts exhibiting sex-biased expression are involved in monocarboxylic acid metabolic processes, organic anion transport, and organic acid transport. The ATAC-seq method on microdissected tubules captured chromatin accessibility. Many of the more than 7000 differentially accessible DNA regions identified were in distal regions. Motif analyses revealed a lack of direct involvement of estrogen receptors or the androgen receptor (absence of canonical hormone response elements), suggesting an indirect regulatory role of sex hormones. Instead, analyses identified several transcription factors (TFs) ( Tead1 , Nfia/b , and Pou3f3 ) whose interplay with proximal tubule-specific TFs ( e.g. , Hnf1b , Hnf4a ) may contribute to sex differences. Finally, the whole-kidney proteome was correlated with the transcriptome, and many sex-biased proteins ( e.g. , Cyp2e1, Acsm2/3) were identified. Conclusions Sex-dependent cis-regulatory elements interact with TFs in ways that lead to sex-biased gene expression in proximal tubule cells. These data are provided as a user-friendly web page at https://esbl.nhlbi.nih.gov/MRECA/PT/.
Kidney Genetics: Continuing Discoveries and a Roadmap to the Clinic
Authors: John R. Sedor
Journal: Journal of the American Society of Nephrology (2023)

Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_04_03_JASN2022060725.mp3
Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway
Authors: Martin R. Späth, K. Johanna R. Hoyer-Allo, Lisa Seufert, Martin Höhne, Christina Lucas, Theresa Bock, Lea Isermann, Susanne Brodesser, Jan-Wilm Lackmann, Katharina Kiefer, Felix C. Koehler, Katrin Bohl, Michael Ignarski, Petra Schiller, Marc Johnsen, Torsten Kubacki, Franziska Grundmann, Thomas Benzing, Aleksandra Trifunovic, Marcus Krüger, Bernhard Schermer, Volker Burst, Roman-Ulrich Müller
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort. Background Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. Methods Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation. Results We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans. Conclusions CR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.
Expression of Class II Human Leukocyte Antigens on Human Endothelial Cells Shows High Interindividual and Intersubclass Heterogeneity
Authors: Stéphanie Béland, Olivier Désy, Rania El Fekih, Meagan Marcoux, Marie-Pier Thivierge, Jean-Simon Desgagné, Eva Latulippe, Julie Riopel, Eric Wagner, Helmut G. Rennke, Astrid Weins, Melissa Yeung, Isabelle Lapointe, Jamil Azzi, Sacha A. De Serres
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Donor-specific antibodies against class II HLA are a major cause of chronic kidney graft rejection. Nonetheless, some patients presenting with these antibodies remain in stable histological and clinical condition. This study describes the use of endothelial colony-forming cell lines to test the hypothesis of the heterogeneous expression of HLA molecules on endothelial cells in humans. Flow cytometry and immunofluorescence staining revealed substantial interindividual and interlocus variability, with HLA-DQ the most variable. Our data suggest that the expression of HLA class II is predicted by locus. The measurement of endothelial expression of HLA class II in the graft could present a novel paradigm in the evaluation of the alloimmune risk in transplantation and certain diseases. Background HLA antigens are important targets of alloantibodies and allospecific T cells involved in graft rejection. Compared with research into understanding alloantibody development, little is known about the variability in expression of their ligands on endothelial cells. We hypothesized individual variability in the expression of HLA molecules. Methods We generated endothelial colony forming cell lines from human peripheral blood mononuclear cells ( n =39). Flow cytometry and immunofluorescence staining were used to analyze the cells, and we assessed the relationship between HLA-DQ expression and genotype. Two cohorts of kidney transplant recipients were analyzed to correlate HLA-DQ mismatches with the extent of intragraft microvascular injury. Results Large variability was observed in the expression of HLA class II antigens, not only between individuals but also between subclasses. In particular, HLA-DQ antigens had a low and heterogeneous expression, ranging from 0% to 85% positive cells. On a within-patient basis, this expression was consistent between endothelial cell colonies and antigen-presenting cells. HLA-DQ5 and -DQ6 were associated with higher levels of expression, whereas HLA-DQ7, -DQ8, and -DQ9 with lower. HLA-DQ5 mismatches among kidney transplant recipients were associated with significant increase in graft microvascular. Conclusion These data challenge the current paradigm that HLA antigens, in particular HLA class II, are a single genetic and post-translational entity. Understanding and assessing the variability in the expression of HLA antigens could have clinical monitoring and treatment applications in transplantation, autoimmune diseases, and oncology.
Impaired Endosome Maturation Mediates Tubular Proteinuria in Dent Disease Cell Culture and Mouse Models
Authors: Katherine E. Shipman, Catherine J. Baty, Kimberly R. Long, Youssef Rbaibi, Isabella A. Cowan, Mona Gerges, Allison L. Marciszyn, Ossama B. Kashlan, Roderick J. Tan, Aurélie Edwards, Ora A. Weisz
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Loss of function of the 2Cl − /H + antiporter ClC-5 in Dent disease causes an unknown impairment in endocytic traffic, leading to tubular proteinuria. The authors integrated data from biochemical and quantitative imaging studies in proximal tubule cells into a mathematical model to determine that loss of ClC-5 impairs endosome acidification and delays early endosome maturation in proximal tubule cells, resulting in reduced megalin recycling, surface expression, and half-life. Studies in a Dent mouse model also revealed subsegment-specific differences in the effects of ClC-5 knockout on proximal tubule subsegments. The approach provides a template to dissect the effects of mutations or perturbations that alter tubular recovery of filtered proteins from the level of individual cells to the entire proximal tubule axis. Background Loss of function of the 2Cl − /H + antiporter ClC-5 in Dent disease impairs the uptake of filtered proteins by the kidney proximal tubule, resulting in tubular proteinuria. Reduced posttranslational stability of megalin and cubilin, the receptors that bind to and recover filtered proteins, is believed to underlie the tubular defect. How loss of ClC-5 leads to reduced receptor expression remains unknown. Methods We used biochemical and quantitative imaging data to adapt a mathematical model of megalin traffic in ClC-5 knockout and control cells. Studies in ClC-5 knockout mice were performed to describe the effect of ClC-5 knockout on megalin traffic in the S1 segment and along the proximal tubule axis. Results The model predicts that ClC-5 knockout cells have reduced rates of exit from early endosomes, resulting in decreased megalin recycling, surface expression, and half-life. Early endosomes had lower [Cl − ] and higher pH. We observed more profound effects in ClC-5 knockout cells expressing the pathogenic ClC-5 E211G mutant. Alterations in the cellular distribution of megalin in ClC-5 knockout mice were consistent with delayed endosome maturation and reduced recycling. Greater reductions in megalin expression were observed in the proximal tubule S2 cells compared with S1, with consequences to the profile of protein retrieval along the proximal tubule axis. Conclusions Delayed early endosome maturation due to impaired acidification and reduced [Cl − ] accumulation is the primary mediator of reduced proximal tubule receptor expression and tubular proteinuria in Dent disease. Rapid endosome maturation in proximal tubule cells is critical for the efficient recovery of filtered proteins.
Pancreatic microexons regulate islet function and glucose homeostasis
Authors: Jonàs Juan-Mateu, Simon Bajew, Marta Miret-Cuesta, Luis P. Íñiguez, Amaya Lopez-Pascual, Sophie Bonnal, Goutham Atla, Sílvia Bonàs-Guarch, Jorge Ferrer, Juan Valcárcel, Manuel Irimia
Journal: Nature Metabolism (2023)
Human striatal glia differentially contribute to AD- and PD-specific neurodegeneration
Authors: Jinbin Xu, Huifangjie L. Farsad, Yiran Hou, Kia Barclay, Ben Anthony Lopez, Shinnosuke Yamada, Ibrahim Olabayode Saliu, Yiming Shi, William C. Knight, Randall J. Bateman, Tammie L. S. Benzinger, Jason J. Yi, Qingyun Li, Ting Wang, Joel S. Perlmutter, John C. Morris, Guoyan Zhao
Journal: Nature Aging (2023)
Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis
Authors: Jeongmin Park, So-Young Rah, Hyeong Seok An, Jong Youl Lee, Gu Seob Roh, Stefan W Ryter, Jeong Woo Park, Chae Ha Yang, Young-Joon Surh, Uh-Hyun Kim, Hun Taeg Chung, Yeonsoo Joe
Journal: Metabolism (2023)
Laparoscopic and endoscopic combined surgery to treat a large superficial nonampullary duodenal tumor
Authors: Diego de Frutos Rosa, Jose Santiago García, Jose L. Lucena, María D. Chaparro, María R. Sánchez Yuste, Ignacio J. Omella, Alberto Herreros de Tejada
Journal: Endoscopy (2023)

Endoscopic resection of large superficial nonampullary duodenal tumors is clinically challenging as the unique anatomical features of the duodenum (thin wall, narrow lumen, exposure to biliary and pancreatic fluids, and small operating space) increase the risks of intra- and post-procedural complications [1]. As conventional surgical methods of resecting superficial nonampullary duodenal tumors are associated with high morbidity and mortality [2], novel combined laparoscopic and endoscopic approaches have recently been developed in specialized centers in an attempt to overcome these limitations [3] [4].
The clinical value of Aspergillus-specific IgG antibody test in the diagnosis of nonneutropenic invasive pulmonary aspergillosis
Authors: Yajie Lu, Lulu Liu, Hongxing Li, Bilin Chen, Yu Gu, Li Wang, Chunlai Feng, Cheng Chen, Yanbin Chen, Wenkui Sun, Xuefan Cui, Min Cao, Yujian Tao, Jinjin Zhong, Huanhuan Zhong, Yueyan Ni, Yuchen Cai, Mengyue Song, Xiaoguang Liu, Yi Shi, Xin Su
Journal: Clinical Microbiology and Infection (2023)
“Snare-pulley” clip-with-line technique to prevent polyp migration after endoscopic resection of a polyp in the third portion of the duodenum
Authors: Yuki Okubo, Takashi Kanesaka, Koji Higashino, Noriya Uedo, Tomoki Michida, Ryu Ishihara
Journal: Endoscopy (2023)

Endoscopic resection of a duodenal tumor carries a risk of loss of the resected specimen because peristalsis and gravity encourage its migration deep into the third part of the duodenum, which cannot generally be reached with an endoscope. The clip-with-line technique, using a double-channel endoscope, has been reported to be useful in avoiding the loss of the specimen [1]; however, the double-channel endoscope is a special instrument and not available at all institutions. We demonstrate a "snare-pulley" clip-with-line technique, which is a technique to prevent polyp migration that uses a conventional single-channel endoscope ([Video 1]).